Process for preparing 1,2,5-thiadiazole containing ethers

ABSTRACT

The presently claimed process provides a method for preparing compounds of the formula ##STR1## phosphorous (III) compound and a diester of azodicarboxylate.

FIELD OF THE INVENTION

The present invention relates to a process for making key intermediates useful for the synthesis of therapeutically active compounds.

BACKGROUND OF THE INVENTION

This invention provides a process for preparing key intermediates useful for the preparation of heterocyclic compounds. Such compounds include, but are not limited to azacyclic and azabicyclic compounds which are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease.

The process of this invention is particularly useful for preparing intermediates which are useful for making compounds of formula I'. The formula I' compounds exhibit muscarinic cholinergic agonist activity. Such compounds have the following structure: ##STR2## wherein W is oxygen or sulphur,

R is hydrogen, amino, halogen, NHR⁶ NR⁶ R⁷, R⁴, --OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂ -(cycloalkylalkyl) wherein R⁴ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF₃, --CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, --CH₃, --CONH₂ or --CSNH₂ ; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, --CF₃, --CONH₂ or --CSNH₂ ; or

R is --OR⁵ Y, --SR⁵ Y, OR⁵ --Z--Y, --SR⁵ ZY, --O--R⁵ --Z--R⁴ or --S--R⁵ --Z--R⁴ wherein Z is oxygen or sulphur, R⁵ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, and Y is a 5 or 6 membered heterocyclic group; and

G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR3## or G can optionally be substituted C₃ -C₈ cycloalkyl or optionally substituted C₁₋₆ -alkyl wherein the substitution is --NR⁶ R⁷ ;

R⁶ and R⁷ independently are hydrogen, C₁₋₆ -alkyl, R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R¹ and R² independently are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, C₁₋₅ -alkyl substituted with --OH, --COR^(6'), CH₂ --OH, halogen, --NH₂, carboxy, or phenyl;

R³ is hydrogen, C₁₋₅ -alkyl, C₂₋₅ -alkenyl or C₂₋₅ -alkynyl;

n is 0, 1 or 2;

m is 0,1 or 2;

p is 0, 1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

....... is a single or double bond.

The present invention provides a process for making key intermediates which are useful for making heterocyclic compounds.

Further, the process may be completed via a convenient, one pot synthesis. Certain of the processes claimed herein provide a method for inverting the stereochemistry at the carbon bearing the hydroxyl group in the G substituent described supra. Such inverted stereochemistry can be important for the commercial development of pharmaceutically active compounds.

SUMMARY OF THE INVENTION

A process for preparing a compound of formula 1 ##STR4## wherein R' is selected from the group consisting of hydrogen, halogen, NR⁶ R⁷, R⁴, --OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂ -(cycloalkylalkyl);

R⁴ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF₃, --CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, or --CF₃ ; or

R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, and --CF₃ ; or

R' selected from the group consisting of --OR⁵ Y, --SR⁵ Y, OR⁵ --Z--Y, --SR⁵ ZY, --O--R⁵ --Z--R⁴ and --S--R⁵ --Z--R⁴ ;

Z is oxygen or sulphur,

R⁵ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, and C₂₋₁₅ -alkynyl;

Y is a 5 or 6 membered heterocyclic group;

R^(1') is selected from the group consisting of phenyl, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl and (NR^(2'))₃ ;

R^(2') and R^(3') are independently selected from the group consisting of hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, and C₁₋₅ -alkyl substituted with one or more selected from the group consisting of halogen and phenyl;

W is oxygen or sulphur;

G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR5## or G can optionally be substituted C₃ -C₈ cycloalkyl or optionally substituted C₁₋₆ -alkyl wherein the substitution is --NR⁶ R⁷ ;

R⁶, and R⁷ independently are C₁₋₆ -alkyl; or

R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R¹ and R² are independently selected from hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, and C₁₋₅ -alkyl substituted with one or more independently selected from the group consisting of --COR^(6'), halogen, and phenyl;

R^(6') is hydrogen or C₁ -C₃ alkyl;

R³ is selected from the group consisting of C₁₋₅ -alkyl, C₂₋₅ -alkenyl and C₂₋₅ -alkynyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

....... is a single or double bond;

comprising contacting a compound of the formula 2 ##STR6## wherein R' is defined above; with a compound of the formula G--OH, a phosphorous (III) compound, and a diester of azodicarboxylate.

Additionally, this invention provides a process for preparing a compound of formula 3 ##STR7## wherein R¹¹ and R¹² are independently selected from the group consisting of hydrogen, R⁴, and G, provided that at least one of the group consisting of R¹¹ and R¹² is selected from the group consisting of R⁴ and G;

R⁴ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF₃, --CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, or --CF₃ ; or

R⁵ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, and C₂₋₁₅ -alkynyl;

Y is a 5 or 6 membered heterocyclic group;

G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR8## or G can optionally be substituted C₃ -C₈ cycloalkyl or optionally substituted C₁₋₆ -alkyl wherein the substitution is --NR⁶ R⁷ ;

R⁶, and R⁷ independently are C₁₋₆ -alkyl; or

R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R¹ and R² are independently selected from hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, and C₁₋₅ -alkyl substituted with one or more independently selected from the group consisting of --COR^(6'), halogen, and phenyl;

R^(6') is hydrogen or C₁ -C₃ alkyl;

R³ is selected from the group consisting of C₁₋₅ -alkyl, C₂₋₅ -alkenyl and C₂₋₅ -alkynyl;

n is 0, 1 or 2;

m is 0,1 or 2;

p is 0,1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

....... is a single or double bond;

comprising contacting a compound of the formula 4 ##STR9## R¹³ and R¹⁴ are each independently selected from the group consisting of hydrogen, G, and R⁴ provided that at least one selected from the group consisting of R¹³ and R¹⁴ is hydrogen;

with a phosphorous (III) compound and a diester of azodicarboxylate.

Further, this invention provides a process for making compounds of formula XIII ##STR10## wherein W is oxygen or sulphur; G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR11## or G can optionally be substituted C₃ -C₈ cycloalkyl or optionally substituted C₁₋₆ -alkyl wherein the substitution is --NR⁶ R⁷ ;

R¹ and R² independently are selected from the group consisting of hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, and C₁₋₅ -alkyl substituted with one or more independently selected from the group consisting of --COR^(6'), halogen, and phenyl;

R^(6') is hydrogen or C₁ -C₃ alkyl;

R³ is selected from the group consisting of C₁₋₅ -alkyl, C₂₋₅ -alkenyl and C₂₋₅ -alkynyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

....... is a single or double bond;

R⁶ and R⁷ independently are C₁₋₆ -alkyl; or

R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R¹⁹ is selected from the group consisting of R⁷, --OR⁷, --SR⁷, --SOR⁷, --SO₂ R⁷, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂ -(cycloalkylalkyl);

R⁷ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF₃, --CN, Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, and --CF₃ ;

provided that at least one alkyl atom of R¹⁹ is substituted with a hydroxyl group or R¹⁹ is selected from the group consisting of --OR⁸ Y, --SR⁸ Y, OR⁸ --Z--Y, --SR⁸ ZY, --O--R⁸ --Z--R⁷ and --S--R⁸ --Z--R⁷ provided that each --OR⁸ Y, OR⁸ --Z--Y, --SR⁸ ZY, --O--R⁸ --Z--R⁷ and --S--R⁸ --Z--R⁷ is substituted with an alkylhydroxyl substituent;

Y is a 5 or 6 membered heterocyclic group;

Z is oxygen or sulphur;

R⁸ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl and C₂₋₁₅ -alkynyl;

aryl and heteroaryl is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, C₁₋₄ -alkylthio, C₁₋₄ -alkylsulfone, C₁₋₄ -alkylsulfoxide, --OCF₃, NO₂, N(R⁷)₂, and --CF₃ ;

R¹⁵ is selected from the group consisting of aryl and heteroaryl; wherein aryl or heteroaryl is optionally independently substituted with one or more selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, C₁₋₄ -alkylthio, C₁₋₄ -alkylsulfone, C₁₋₄ -alkylsulfoxide, --OCF₃, NO₂, N(R⁷)₂, and --CF₃ ;

comprising contacting a compound of the formula (XIV) ##STR12## with a R¹⁵ OH compound, a phosphorous (III) compound, and a diester of azodicarboxylate;

wherein G(CH₂)_(r) W, R¹⁹, and R¹⁵ are as defined supra.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enatiomeric, and racemic forms of the compounds of this invention.

As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.

As used herein with reference to the G substituent, the --(CH₂)_(r) --W-thiadiazole moiety can be attached at any carbon atom of the azacyclic or azabicyclic ring. Further, R¹ and R² of the G substituent may be present at any position, including the point of attachment of the --(CH₂)_(r) --W-thiadiazole moiety.

As used herein with reference to the G substituent, the phrase "R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to 6-member ring" means that R⁶ and R⁷ are each independently hydrogen, C₁ -C₆ alkyl wherein the R⁶ and R⁷ groups may optionally join to form a 4- to 6-member ring including the nitrogen. For example, optionally joined groups include, but are not limited to: ##STR13##

As used herein the phrase "interacting with a muscarinic cholinergic receptor" shall include compounds which block muscarinic cholinergic receptors or modulate such receptors. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a muscarinic cholinergic receptor.

As used herein the phrase "one or more selected from" refers to from 1-3 substituents. The term shall further preferredly refer to from 1-2 substituents.

As used herein, the term "alkoxide metal" means a metal suitable for alkoxide formation. Such alkoxide metals include, but are not limited to, Li⁺, K⁺, Na⁺, Cs⁺, and Ca⁺⁺. Especially preferred alkoxide metals include Li⁺, K⁺, and Na⁺. As used herein the term "alkaline metal hydroxide" shall include, but are not limited to Li⁺, K⁺, Na⁺, Cs⁺, and Ca⁺⁺. Preferred alkoxide metal include Li⁺, K⁺, and Na⁺.

As used herein, the term "halogen" or the term "HAL" means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and I.

As used herein the phrase "one or more selected from" shall more preferredly refer to from 1-3 substituents. The term shall further preferredly refer to from 1-2 substituents.

As used herein the term "phosphorous(III) compound" has the art accepted meaning of the term. For example, the term includes, but is in no way limited to, triphenylphosphine, tri(p-toluyl) phosphine, tributyl phosphine, tri(p-dimethylaminiophenyl) phosphine, triethyl phosphine, and trimethyl phosphine. The artisan can choose other appropriate phosphorous(III) compounds using methods and literature references which are commonly available to the chemist artisan.

As used herein the term "diester of azodicarboxylate" has the art accepted meaning of the term. For example, the term includes, but is in no way limited to diethylazodicarboxylate, dimethylazodicarboxylate, diisopropylazodicarboxylate, and di-tertbutylazodicarboxylate. The skilled chemist can determine other appropriate diesters of azodicarboxylate using methods and literature readily available to the chemist artisan.

The terms "C₁ -C_(n') alkyl" wherein n' can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical C₁ -C₆ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The terms "C₂ -C_(n') alkenyl" wherein n' can be from 3 through 10, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl (--CH₂ --CH═CH₂), 1,3-butadienyl, (--CH═CHCH═CH₂), 1-butenyl (--CH═CHCH₂ CH₃), hexenyl, pentenyl, and the like.

The term "C₂ -C₅ alkynyl" refers to an unsaturated branched or linear group having from 2 to 5 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like.

The terms "halogen(C₁ -C₆)alkyl" and "halogen(C₂ -C₆)alkenyl" refer to alkyl or alkenyl substituents having one or more independently selected halogen atoms attached at one or more available carbon atoms. These terms include, but are not limited to, chloromethyl, 1-bromoethyl, 2-bromoethyl, 1,1,1-trifluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, trifluoroethylenyl, 3-bromopropyl, 3-bromo-1-propenyl, 2-bromopropyl, 2-bromo-1-propenyl, 3-chlorobutyl, 3-chloro-2-butenyl, 2,3-dichlorobutyl, 1-chloroethylenyl, 2-chloroethylenyl, 5-fluoro-3-pentenyl, 3-chloro-2-bromo-5-hexenyl, 3-chloro-2-bromobutyl, trichloromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl, 1,4-dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl, 1,1-dichloropropyl, and the like.

The term "C₂ -C₁₀ alkanoyl" represents a group of the formula C(O) (C₁ -C₉) alkyl. Typical C₂ -C₁₀ alkanoyl groups include acetyl, propanoyl, butanoyl, and the like.

The term "(C₁ -C₆ alkyl) amino" refers to a monoalkylamino groups. Examples of such groups are methylamino, ethylamino, iso-propylamino, n-propylamino, (n-propyl)amino, (iso-propyl)amino, n-propylamino, t-butylamino, and the like.

The term "C₃ -C_(n) cycloalkyl" wherein n=4-8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "substituted(C₅ -C_(n')) cycloalkyl" refers to a cycloalkyl groups as described supra wherein the cycloalkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halogen, halogen(C₁ -C₆)alkyl, halogen(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, CO₂ R²⁰, (C₁ -C₆ alkyl) amino, --SR²⁰, and OR²⁰ ; wherein R²⁰ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl.

The term "C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl" represents an alkyl group substituted at a terminal carbon with a C₃ -C₈ cycloalkyl group. Typical cycloalkylalkyl groups include cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl, and the like.

The term "C₅ -C₈ cycloalkenyl" represents an olefinically unsaturated ring having five to eight carbon atoms. Such groups include, but are not limited to, cyclohexyl-1,3-dienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexyl-1,4-dienyl, cycloheptyl-1,4-dienyl, cyclooctyl-1,3,5-trienyl and the like.

The term "substituted (C₅ -C₈) cycloalkenyl" refers to a cycloalkenyl group as described supra, wherein the cycloalkenyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halogen, halogen(C₁ -C₆)alkyl, halogen(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, COR²⁰, C₂ -C₁₀ alkanoyl, C₇ -C₁₆ arylalkyl, CO₂ R²⁰, (C₁ -C₆ alkyl) amino, --SR²⁰, and --OR²⁰ ; wherein R²⁰ is selected from the group consisting of C₁₋₁₅ - alkyl, C₂₋₁₅ -alkenyl, and C₂₋₁₅ -alkynyl.

The term "C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl" represents a C₁ -C₃ alkyl group substituted at a terminal carbon with a C₅ -C₈ cycloalkenyl group.

As used herein, the phrase "5 or 6 membered heterocyclic group" means a group containing from one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with C₁₋₆ -alkyl, --CF₃, phenyl, benzyl or thienyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group. The phase "5 or 6 membered heterocyclic group" includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocycles having three heteroatoms (e.g. triazoles, thiadiazoles); 5-membered heterocycles having 3-heteroatoms; 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heterocycles with two heteroatoms (e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heterocycles with three heteroatoms (e.g. 1,3,5-triazine); and 6-member heterocycles with four heteroatoms. Particularly preferred are thiophenes, pyridines, and furans.

The term "heteroaryl" refers to a group which is a 5 or 6 membered heterocycle containing one to four N, O, or S atoms or a combination thereof.

As used herein the term "carboxy" refers to a substituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group.

As used herein the term "aryl" means an organic radical derived from an aromatic hydrocarbon by the removal of one atom; e.g., phenyl or naphthyl. Most preferably, aryl refers to C₆ -C₁₀ aryl, wherein the aryl ring system, including any alkyl substitutions, comprises from 6 to 10 carbon atoms; e.g., phenyl, 3,3-dimethylphenyl, naphthyl, and the like. The aryl radical may be substituted by one or two C₁ -C₆ straight or branched alkyl. The term "aryl(C₁ -C₃)alkyl" refers to any aryl group which is attached to the parent moiety via the alkyl group.

As used herein the phrase "one or more selected from" refers more preferredly to from 1-3 substituents. The term further preferredly refers to from 1-2 substituents.

Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

The starting materials for the illustrated processes are commercially available or may be prepared using methods known to the skilled artisan.

Certain compounds of this invention may more preferredly be prepared by a process using a hydroxyalkylamine (G--OH) wherein G has the meaning defined supra. in the presence of a phosphorous(III) compound, for example, but not in any way limited to triphenylphosphine, and a diester of azodicarboxylate, for example, but not in any way limited to diethylazodicarboxylate to give the 1,2,5-thiadiazoyloxyalkylamine as illustrated by Scheme IV. ##STR14##

The G groups are as defined supra. The R' is selected from the group consisting of hydrogen, halogen, NR⁶ R⁷, R⁴, --OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂ -(cycloalkylalkyl);

R⁴ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF₃, --CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, or --CF₃ ; or

R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, and --CF₃ ; or

R' selected from the group consisting of --OR⁵ Y, --SR⁵ Y, OR⁵ --Z--Y, --SR⁵ ZY, --O--R⁵ --Z--R⁴ and --S--R⁵ --Z--R⁴ ;

Z is oxygen or sulphur;

R⁵ is selected from the group consisting of C₁₋₁₅ -alkyl,

C₂₋₁₅ -alkenyl, and C₂₋₁₅ -alkynyl;

Y is a 5 or 6 membered heterocyclic group;

R^(1') is selected from the group consisting of phenyl, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl and (NR^(2'))₃ ;

R^(2') and R^(3') are independently selected from the group consisting of hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, and C₁₋₅ -alkyl substituted with one or more selected from the group consisting of halogen and phenyl;

W is oxygen or sulphur;

G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR15## or G can optionally be substituted C₃ -C₈ cycloalkyl or optionally substituted C₁₋₆ -alkyl wherein the substitution is --NR⁶ R⁷ ;

R⁶, and R⁷ independently are C₁₋₆ -alkyl; or

R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R¹ and R² are independently selected from hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, and C₁₋₅ -alkyl substituted with one or more independently selected from the group consisting of --COR^(6'), halogen, and phenyl;

R^(6') is hydrogen or C₁ -C₃ alkyl;

R³ is selected from the group consisting of C₁₋₅ -alkyl, C₂₋₅ -alkenyl and C₂₋₅ -alkynyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

....... is a single or double bond;

Preferred R^(1') groups include phenyl, C₁₋₁₅ -alkyl, and (NR^(2'))₃. The process of Scheme IV is particularly advantageous because the process provides a method for inverting the stereochemistry at the carbon bearing the hydroxyl group in G.

Another new process illustrated by Scheme V, involves the sequential reaction of 3,4-dihydroxy-1,2,5-thiadiazole with G--OH wherein G is defined as defined supra. in the presence of a phosphorous(III) compound and a diester of azodicarboxylate to give an unisolated hydroxy-1,2,5-thiadiazole ether I" followed by reaction of I" with R⁴ OH where R⁴ is defined as supra. with phosphorous(III) compounds and a diester of azodicarboxylate to give the diethers of 3,4-dihydroxy-1,2,5-thiadiazole which are useful as muscarinic agonists and antagonists. (See, Org. Prep. & Procedures 1969, 1, 255-258). The substituents illustrated in Scheme V are as defined supra. ##STR16##

Alternatively, the order of addition of the alcohols may be reversed as shown above to give unisolated hydroxy-1,2,5-thiadiazole ether II which is subsequently converted to the same final muscarinic active compound.

The process illustrated by Scheme VI emcompassed the reaction of a phenol or hydroxyheteroaryl compound with compound III in the presence of a phosphorous(III) compound and a diester of azodicarboxylate to give compound IV. ##STR17##

In compound III, G(CH₂)_(r) W is as defined supra. and R^(6') is selected from the group consisting of R⁷, --OR⁷, --SR⁷, --SOR⁷, --SO₂ R⁷, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂ -(cycloalkylalkyl);

R⁷ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF₃, --CN, Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, and --CF₃ ;

provided that at least one alkyl atom of R^(6') is substituted with a hydroxyl group or R^(6') is a substituent selected from the group consisting of --OR⁸ Y, --SR⁸ Y, OR⁸ --Z--Y, --SR⁸ ZY, --O--R⁸ --Z--R⁷ and --S--R⁸ --Z--R⁷ wherein each --OR⁸ Y, --SR⁸ Y, OR⁸ --Z--Y, --SR⁸ ZY, --O--R⁸ --Z--R⁷ and --S--R⁸ --Z--R⁷ is substituted with a alkylhydroxyl;

Y is a 5 or 6 membered heterocyclic group;

Z is oxygen or sulphur;

R⁸ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl;

aryl and heteroaryl is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, C₁₋₄ -alkylthio, C₁₋₄ -alkylsulfone, C₁₋₄ -alkylsulfoxide, --OCF₃, NO₂, N(R⁷)₂, and --CF₃ ; heteroaryl group is a 5 or 6 membered heterocycle containing one to four N, O, or S atoms or a combination thereof.

The compounds prepared using the process of this invention can be used for making pharmaceutically active compounds as illustrated by the following Schemes II, and III.

Compounds of Formula I may be prepared using the process illustrated in the following Scheme II ##STR18##

As used in Scheme II, Q may be N, O or S; R²⁴ is selected from the group consisting of hydrogen, R⁴, R⁵, R⁶, and R⁷ ; R²⁵ is selected from the group consisting of SOR⁴ and SO₂ R⁴ ; all other meanings are as defined supra.

Additional compounds of Formula I may be prepared using the process illustrated by Scheme III. ##STR19##

As used in Scheme III, Hal, W, r, and G are as defined supra. As used in Scheme III, R²² and R²³ are independently selected from the group consisting of hydrogen, R⁶ and R⁷.

The concentration of the reactants is not critical. The art worker can alter the concentration of the reactants to achieve the desired rate of reaction and product yield.

The length of time for carrying out the processes described are not critical. As is always the case in chemistry, the rate of the reaction depends on a variety of factors, such as the temperature and the exact compound which is to be prepared. The course of the reaction may be followed using methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) and nuclear magnetic resonance spectroscopy (NMR) to detect the degree of completion of the reaction. The operator may obtain maximum yields using the process by extending the reaction time. Alternatively, the operator may wish to obtain maximum throughput by cutting off the reaction at the point at which it reaches an economical degree of completion.

When the product of a step in the following process is an oil, it may be isolated by standard methods. Such methods include distillation, flash chromatography, HPLC and the like.

The intermediates and processes of the present invention are useful for preparing compounds having beneficial muscarinic receptor activity.

The following example is provided for illustrative purposes only, and is not intended to limit the scope of the claimed invention in any way.

PREPARATION 1 3-Chloro-4-(1-butylthio)-1,2,5-thiadiazole

Cyanogen (36 g, 0.69 mol) was bubbled into ether (250 mL) maintained at -10° C. To the solution was added dropwise diethylamine (3 mL) followed by dropwise addition of 1-butylthiol (47 mL, 0.64 mol) at such a rate that the temperature did not exceed -5° C. The reaction was maintained below 0° C. for 5 h then stirred at ambient overnight. Ether was distilled from the reaction until the pot temperature reached 50° C. The reaction was cooled to ambient and then added dropwise to a solution of sulfur monochloride (55 mL, 0.688 mol) in DMF (50 mL) that was cooled to 5° C. Cooling was removed and reaction was stirred overnight. The reaction was cooled in an ice-water bath and excess sulfur monochloride destroyed by careful addition of H₂ O while maintaining the temperature below 40° C. The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H₂ O, aqueous NaHCO₃, brine, dried, and the solvent evaporated. The residue was distilled at 2 mm Hg to give a yellow liquid (24.6 g), b.p. 105-110° C. (Compound 1).

PREPARATION 2 3-Chloro-4-ethoxy-1,2,5-thiadiazole

A solution of ethanol (60 mL, 1.02 mol) and triethylamine (1.5 mL) was cooled to -8° C. and cyanogen (59 g, 1.13 mol) was slowly bubbled through the solution while maintaining the temperature below 2° C. The reaction was then added dropwise to a solution of DMF (275 mL) and sulfur monochloride (225 mL, 2.81 mol) that was cooled to 5° C. while maintaining the temperature of the DMF solution below 10° C. Cooling was removed and the reaction was stirred over night. The reaction was cooled in an ice-water bath and the excess sulfur monochloride destroyed by dropwise addition of H₂ O such that the temperature did not exceed 30° C. Additional H₂ O (400 mL) was added and the reaction internally steam distilled until the distillate was almost homogeneous. The distillate was extracted with hexane (3 X) and the combined extracts washed with H2O, aqueous NaHCO₃, brine, dried, and the solvent carefully evaporated. The liquid residue was distilled at 21 mm Hg to give a clear liquid (154.3 g), b.p. 88-93° C. (Compound 93).

EXAMPLE 1 (±)-3-(2-Methylthioethyl)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole

A solution of 3-(2-methylthioethyl)-4-hydroxy-1,2,5-thiadiazole (0.45 g) and triphenylphosphine (0.7 g) was cooled in ice-water as diethyldiazodicarboxylate (0.4 mL) was added dropwise. After addition, (±)-1-azabicyclo[2.2.2]octan-3-ol (0.33 g) was added, cooling removed, and reaction stirred for 1 hour. The solvent was evaporated, residue suspended in water, the mixture acidified and washed with ether. The aqueous solution was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, the residue purified by radial chromotography eluting with 10%-EtOH-1%--NH₄ OH--CHCl₃, and the product converted to a HCl salt. Recrystallization from acetone gave 0.6 g white crystals, m.p. 177-178° C. (Compound 99).

The following compounds were synthesized in substantially the same manner as Compound 99.

EXAMPLE 2 (±)-3-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole

A sample of 3-Hydroxy-1,2,5-thiadiazole (0.28 g), triphenylphospine (0.7 g), diethyldiazodicarboxylate (0.4 mL), and (±)-1-azabicyclo[2.2.2]octan-3-ol (0.33 g) gave the hydrochloride salt of (±)-3-(1-azabicycle[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole, m.p. 240° C. dec. (0.36 g). (Compound 100).

EXAMPLE 3 (±)-3-Hexyl-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole

A sample of 3-Hexyl-4-Hydroxy-1,2,5-thiadiazole (0.93 g), triphenylphospine (1.31 g), diethyldiazodicarboxylate (0.8 mL), and (±)-1-azabicyclo[2.2.2]octan-3-ol (0.64 g) gave the hydrochloride salt of (±)-3-hexyl-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole, m.p. 163-164° C dec. (1.11 g). (Compound 101).

EXAMPLE 4 (±)Exo-3-Butylthio-4-(1-azabicyclo[2.2.1]heptyl-3-oxy)-1,2,5-thiadiazole

A solution of triphenylphosphine (0.7 g) and Compound 300 (0.5 g) in THF (20 mL) was cooled in ice-water. Diethyl diazodicarboxylate (0.4 mL) was added dropwise followed by addition of (±)endo-3-hydroxy-1-azabicyclo[2.2.1]heptane (0.29 g). Cooling was removed and after 1 h the solvent was evaporated. The residue was suspended in cold water, acidified, and extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 5%-EtOH-0.5% NH₄ OH--CHCl₃ to give a clear oil. The HCl salt crystallized from EtOAc as white crystals (0.44 g), m.p. 147-148° C. (Compound 301).

EXAMPLE 5 (±)exo-3-(1-Azabicyclo[2.2.1]heptyl-3-oxy)-1,2,5-thiadiazole

Prepared in the same manner as Compound 301. (±)Exo-3-(1-azabicyclo[2.2.1]heptyl-3-oxy)-1,2,5-thiadiazole was obtained from 3-hydroxy-1,2,5-thiadiazole (0.14 g), triphenylphosphine (0.35 g), diethyldiazodicarboxylate (0.21 mL) and (±)-endo-1-azabicyclo[2.2.1]heptane-3-ol (0.15 g) as a hydrochloride salt (0.096 g), m.p. 223° C. dec. (Compound 302).

EXAMPLE 6 3-Butylthio-4-hydroxy-1,2,5-thiadiazole

A solution of Compound 1 (20.9 g), DMSO (20 mL) and 2N NaOH (205 mL) was heated to reflux overnight. The solution was cooled to 15° C. and concentrated HCl was added until the pH was 1. The solid was collected, washed with water, and dried to give a solid (17.68 g). Recrystallization from heptane gave white crystals, m.p. 72-72.5° C. (Compound 300).

EXAMPLE 7 3Ethoxy-4-hydroxy-1,2,5-thiadiazole

A mixture of Compound 93 (8.2 g), 2N NaOH (100 mL), and DMSO (10 mL) was heated to reflux over night. The reaction was cooled and extracted with ether. The aqueous fraction was acidified with conc. HCl and cooled 30 min in ice-water. The solid was collected from the resulting mixture by filtration and washed with a small amount of cold water to give white crystals (4.4 g). Recrystallization from heptane gave white flakes, m.p. 104.5-105.5° C. (Compound 303).

EXAMPLE 8 3-Propylthio-4-hydroxy-1,2,5-thiadiazole

A mixture of 3-chloro-4-propylthio-1,2,5-thiadiazole (10 g), 2 N NaOH (100 mL), and DMSO (10 mL) was heated to reflux for 24 h. The solution was cooled and extracted with ether. The aqueous fraction was acidified with conc. HCl and cooled in ice-water for 3 h. The resulting solid was collected, washed with a small amount of cold water to give a white solid (8.15 g). Recrystallization from heptane gave white crystals, m.p. 84-85° C. (Compound 304). 

We claim:
 1. A process for preparing a compound of formula 1 ##STR20## wherein R¹ is hydrogen, halogen, NR⁶ R⁷, R⁴, --OR⁴, --SR⁴, SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl, --Z--C₄₋₁₂ -(cycloalkylalkyl), --OR⁵ Y, --SR⁵ Y, --OR⁵ ZY, --SR⁵ ZY, --OR⁵ ZR⁴, --SR⁵ ZR⁴, phenyl or benzyloxycarbonyl, or phenyl or benzyloxycarbonyl substituted with one or more substituents independently selected from halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, or --CF₃ ;R⁴ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, or C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, --CF₃, --CN, Y, phenyl or phenoxy, or phenyl or phenoxy substituted with one or more substituents independently selected from halo, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, or --CF₃ ; Z is oxygen or sulphur; R⁵ is C₁₋₁₅ -alkylene, C₂₋₁₅ -alkenylene, or C₂₋₁₅ -alkynylene; Y is a 5 or 6 membered heterocyclic group; R⁶ and R⁷ independently are C₁₋₆ -alkyl; or R⁶ and R⁷ together with the nitrogen atom from a 4- to 6-membered ring; G is an azacyclic or azabicyclic ring system selected from: ##STR21## R¹ and R², independently, are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, or C₁₋₅ -alkyl substituted with one or more substituents independently selected from --COR^(6'), halo or phenyl; R^(6') is hydrogen or C₁ -C₃ alkyl; R³ is C₁₋₅ -alkyl, C₂₋₅ -alkenyl or C₂₋₅ -alkynyl; m, n, p and p, independently, are 0, 1 or 2; q is 1 or 2; and - - - is a single or double bond;comprising contacting a compound of formula 2 ##STR22## wherein R' is as defined supra; with a compound of the formula G--OH, a phosphorous(III) compound, and a diester of azodicarboxylate.
 2. A process of claim 1 wherein the phosphorous(III) compound has the formula P(R^(1'))₃, wherein R^(1') is phenyl, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, or N(R^(2'))₂ ; and R^(2') is hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, or C₁₋₅ -alkyl having one or more halo or phenyl substituents.
 3. A process of claim 1 wherein the diester of azodicarboxylate has the formula ##STR23## R^(2') and R^(3'), independently, are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, or C₁₋₅ -alkyl having one or more halo or phenyl substituents.
 4. A process of claim 2 wherein the diester of azodicarboxylate has the formula ##STR24## R^(2') and R^(3'), independently, are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, or C₁₋₅ -alkyl having one or more halogen or phenyl substituents.
 5. A process for preparing a compound of formula 3a ##STR25## wherein R¹¹ is hydrogen or R⁴ ;R⁴ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, or C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, --CF₃, --CN, Y, phenyl or phenoxy, or phenyl or phenoxy substituted with one or more substituents independently selected from halo, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, or --CF₃ ; Y is a 5 or 6 membered heterocyclic group; G is an azacyclic or azabicyclic ring system selected from ##STR26## R⁶ and R⁷ independently are C₁₋₆ -alkyl; or R⁶ and R⁷ together with the nitrogen atom form a 4- to 6-membered ring; R¹ and R², independently, are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, or C₁₋₅ -alkyl substituted with one or more substituents independently selected from --COR^(6'), halo or phenyl; R^(6') is hydrogen or C₁ -C₃ alkyl; R³ is C₁₋₅ -alkyl, C₂₋₅ -alkenyl or C₂₋₅ -alkynyl; m, n, p and p, independently, are 0, 1 or 2; q is 1 or 2; and - - - is a single or double bond;comprising contacting a compound of formula 4 ##STR27## with a phosphorous(III) compound and a diester of azodicarboxylate.
 6. A process of claim 5 wherein the phosphorous (III) compound has the formula P(R^(1'a))₃, wherein R^(1'a) is phenyl, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, or C₁₋₅ -alkyl having one or more --COR^(6'), halo, or phenyl substituents.
 7. A process of claim 5 wherein the diester of azodicarboxylate has the formula ##STR28## R^(2'a) and R^(3'a), independently, are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, or C₁₋₅ -alkyl having one or more --COR^(6'), halo or phenyl substituents.
 8. A process of claim 6 wherein the diester of azodicarboxylate has the formula ##STR29## wherein R^(2'a) and R^(3'a), independently, are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, or C₁₋₅ -alkyl having one or more --COR^(6'), halo or phenyl substituents.
 9. A process of claim 3 wherein the diester of azodicarboxylate is diethyl₋₋ azodicarboxylate.
 10. A process of claim 4 wherein the phosphorous (III) compound is triphenylphosphine.
 11. A process of claim 4 wherein G is unsaturated.
 12. A process of claim 1 wherein R' is R⁴, and R⁴ is C₁₋₆ -alkyl.
 13. A process of claim 7 wherein the diester of azodicarboxylate is diethyl₋₋ azodicarboxylate.
 14. A process of claim 8 wherein the phosphorous (III) compound is triphenylphosphine.
 15. A process of claim 8 wherein G is unsaturated.
 16. A process of claim 5 wherein R' is R⁴, and R⁴ is C₁ -C₆ alkyl.
 17. A process of claim 1 wherein a stereocenter is inverted.
 18. A process of claim 5 wherein a stereocenter is inverted.
 19. A process of claim 7 wherein the phosphorous (III) compound is triphenylphosphine; the diester of azodicarboxylate is diethyl₋₋ azodicarboxylate; and G is an azacyclic or azabicyclic ring.
 20. A process of making a compound of formula XIII ##STR30## wherein W is oxygen or sulphur;G is an azacyclic or azabicyclic ring system selected from: ##STR31## R¹ and R², independently, are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, or C₁₋₅ -alkyl substituted with one or more substituents independently selected from --COR^(6'), halo or phenyl; R^(6') is hydrogen or C₁ -C₃ alkyl; R³ is C₁₋₅ -alkyl, C₂₋₅ -alkenyl or C₂₋₅ -alkynyl; m, n, p and r, independently, are 0, 1 or 2; q is 1 or 2; - - - is a single or double bond; R⁶ and R⁷ independently are C₁₋₆ -alkyl; or R⁶ and R⁷ together with the nitrogen atom form a 4- to 6-membered ring; R¹⁹ is --R⁴ --, --OR⁴ --, --SR⁴ --, --SOR⁴ --, C₃₋₁₀ -cycloalkylene, C₄₋₁₂ -(cycloalkylalkylene), --Z--C₃₋₁₀ -cycloalkylene, --Z--C₄₋₁₂ -(cycloalkylalkylene), --OR⁵ Y--, --SR⁵ Y--, --OR⁵ ZY--, --SR⁵ ZY--, --OR⁵ ZR⁴ -- or --SR⁵ ZR⁴ --; R⁴ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, or C₂₋₁₅ -alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, --CF₃, --CN, Y, phenyl or phenoxy, or phenyl or phenoxy substituted with one or more substituents independently selected from halo, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, or --CF₃ ; Y is a 5 or 6 membered heterocyclic group Z is oxygen or sulphur; R⁵ is C₁₋₁₅ -alkylene, C₂₋₁₅ -alkenylene or C₂₋₁₅ -alkynylene; R¹⁵ is aryl or heteroaryl, or aryl or heteroaryl substituted with one or more substituents independently selected from halo, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, C₁₋₄ -alkylthio, C₁₋₄ -alkylsulfonyl, C₁₋₄ -alkylsulfoxide, --OCF₃, NO₂, N(R⁷)₂, and --CF₃ ; comprising 1) contacting a compound of formula XIV ##STR32## wherein G, r, and W, are as defined supra, and R^(19') is a hydroxyl-substituted group wherein the group is selected from R⁴, --OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl, --Z--C₄₋₁₂ -(cycloalkylalkyl), and the hydroxyl substituent is located on the alkyl component of the R^(19') group; or R^(19') is a hydroxyalkyl-substituted group wherein the group is selected from --OR⁵ Y, --SR⁵ Y, --OR⁵ ZY, --SR⁵ ZY, --OR⁵ ZR⁴ or --SR⁵ ZR⁴ ; with an R¹⁵ OH compound, a phosphorous(III) compound, and a diester of azodicarboxylate; or 2) contacting a compound of formula XIVa ##STR33## wherein R⁴ is as defined supra, with a GOH compound, a phosphorous(III) compound, and a diester of azodicarboxylate. 